1. Field of the Invention
This invention relates to polyvinylpyrrolidone-iodine (PVP-I.sub.2) complexes, and more particularly, to complexes of strongly swellable, lightly crosslinked PVP with iodine that exhibit antiseptic, broad-spectrum antimicrobial activity in a controlled and sustained manner.
2. Description of the Prior Art
Numerous potential pathogens may be present on the skin and exposed tissue. It is desirable for the growth of disease-producing microorganisms to be inhibited and preferaby for these microorganisms to be destroyed so as to control patient infection and encourage wound healing. As a result, the application to the skin or tissue of topical bactericidally active agents has become a standard part of the aseptic technique for wound care.
Iodine is an outstanding microbicide, with an extraordinary range of action. Part of its mode of action is that it is able to penetrate the cell walls of microorganisms rapidly, and block certain essential hydrogen-bonding in amino acids. Also, it has a powerful, oxidizing effect on S--H, group to form a --S--S-- groups, which are essential factors in protein production. It is effective against a wide range of microorganisms, including bacteria, tubercle bacilli (Mycobacteria), fungi, protozoa, lipid and medium viruses, as well as non-lipid and small viruses. Iodine is designated as an intermediate germicide only because spores are not readily killed with weak concentrations. However, iodine has the greatest degerming efficiency compared to the other halogens, chlorine and bromine, since it is deactivated by proteins at least three times slower than chlorine and four times slower than bromine. Therefore, under normal conditions of use where there is the presence of large amounts of dissolved proteins as in blood, serum, or sputum, iodine would not be rendered ineffective. Iodine has the additional advantage that its disinfecting properties are independent of the pH value of its environment. Therefore, unlike chlorine, for example, iodine would not be rendered ineffective in an acid pH. It would likewise not be deactivated quickly in an alkaline pH.
Low concentrations of iodine react relatively slowly as compared with proteins in general and therefore it remains available to react with bacteria to which it generally has a greater affinity. It is in this way that iodine can exhibit its unique advantageous selectivity towards microorganisms while maintaining a very low level of cytotoxicity to the host cells. However, because of iodine's physical and inherent chemical properties, its use as an antiseptic, broad-spectrum antimicrobial has been limited because state of the art delivery methods allows for the liberation of too much free iodine which can be toxic to living cells.
Elemental iodine, in the form of Tincture of Iodine (alcoholic solution), is highly toxic if brought into contact with the body cavity. It causes swelling and bleeding of the mucous membranes. Iodine is therefore generally not impregnated into bandages because of the potential for this corrosive destruction of the skin. A 1% Tincture of Iodine solution can release in excess of 10,000 ppm of iodine into the surrounding tissue environment all at once, when only 0.5-2 ppm of iodine may be required to be antimicrobially effective. Consumption by an adult of 30 grams of Tincture of Iodine can be fatal. Also, elemental iodine is volatile having a high, intrinsic vapor pressure which causes, over time, a loss in germicidal potency. This occurs when the iodine content volatizes from coated surfaces or from antiseptic preparations, especially when exposed to the environment at elevated temperatures.
One example of an attempt to preserve or tame the outstanding antimicrobial activity of iodine, while simultaneously reducing its corrosive toxic and vapor pressure properties, is a two-part dressing, using an iodide salt in one component and an oxidizer in the other which react on moisture contact, liberating iodine, as described by Karns in U.S. Pat. No. 1,867,222. Another example is the use of water soluble complexes of polyvinylpyrrolidone and iodine (PVP/I.sub.2) as disclosed by Lorenz in U.S. Pat. No. 4,128,633. The latter is illustrative of a complex of iodine and an organic carrier commonly known as an "iodophor". This complexing of iodine by PVP harnesses the iodine, thereby controlling its rate of release. However, both these aqueous solution complexes still have limited application in spite of their slower release properties, as their water miscibility with body fluids still causes excess delivery and quick dissipation of the released iodine, resulting in possible cytotoxicity and loss of long time effectiveness.
Iodophors are loose complexes of elemental iodine or triodide, solubilizers, and a polymeric carrier that serves, not only to increase the solubility of the iodine, but also to tame the iodine to provide a sustained release reservoir for the iodine. The carriers, heretofore, have been neutral, water soluble polymers, with mainly polyvinylpyrrolidones as the principal commercialized polymer. Polyether glycols, polyacrylic acids, polyamides, polyoxyalkylenes, starches and polyvinyl alcohol (PVA) also form iodophors. Carriers may also exhibit varying degrees of surface active properties that improve the penetration or wetting characteristics of the solution in use. Upon dilution, these iodophor complexes form micellar aggregates, which are dispersed, upon dilution, with water or bodily fluids, and the iodine linkage to the polymer is progressively weakened until the iodine can be regarded as free to generate antimicrobial concentrations. These iodine complexes in aqueous solution have the advantage over pure, elemental iodine solutions, in that because they are present in far less concentration they greatly reduce irritation to tissue, unpleasant odor, staining of tissue and corrosion of metal surfaces such as surgical instruments, but dissipate relatively quickly because of their miscibility and reaction with body fluids.
Generally, when such a complex is in equilibrium with the aqueous phase, and then diluted, the solution will have increased availability of free iodine within a given fixed volume. These iodophors, because of their water solubility, therefore tend to dissipate their antimicrobial action quickly, because as a solution, they are water miscible with fluids throughout the wound site, and react relatively quickly with serous fluids while reacting with the bacteria. The concentrations of iodine in water-based systems can be much higher than what is required for its antimicrobial intent, and iodine is dissipated by side reactions with body fluids, resulting in the iodine reservoir being prematurely used up and thus allowing recolonization of the wound site.
Compared to Tincture of Iodine, the improved release properties of PVP/I.sub.2 iodophor have resulted in the greater use of iodine in preoperative skin preps, surgical scrubs, washes, douches, lotions and ointments. However, their limited iodine reserves and dilution factors have meant that such iodophors are effective for a given disinfecting purpose for a limited time only. Microorganisms that have survived the initial application, because of limited longevity of the antimicrobial agent, may act as a seed to cause the pathogen population to rise again to its initial level.
Most water miscible broad-spectrum antimicrobials exhibit this deficiency. Continuous application of the antimicrobial agent to the site is therefore required, to inhibit the increase in population. For example, sustained release can be provided, with prolonged antibacterial activity under a plastic, self-adhering surgical drape film. Rosso, in U.S. Pat. No. 4,323,557, describes a process for incorporating N-vinylpyrrolidone (NVP) in the polymeric backbone of a pressure-sensitive adhesive of which the pyrrolidone component serves to complex and slowly release the iodine. The iodophor-based adhesive film provides a sterile operative surface, and acts as a barrier to isolate the incision from contaminating skin flora. This product is for use as an incisible self-adhering drape and is not intended for wound healing dressings or wound packings.
A major disadvantage of PVP/I.sub.2 complexes is that their safe and efficacious antimicrobial action is limited to use on skin or, in some cases, on intact mucosa. This is because their water solubility, as mentioned above, results in rapid and excess releases of free iodine when introduced into the wound site. Considering that as little as 0.2 ppm of iodine is sufficient to kill enteric bacteria (10 minutes at 25.degree. C.), and under the same conditions, 3.5 ppm and 14.6 ppm of iodine, respectively, are sufficient to kill amoebic cysts and enteric viruses, PVP/I.sub.2 complex solutions can instantaneously introduce thousands of excess parts of available iodine in one bolus (i.e., an uncontrolled burst of solution), dependent upon the site. Large concentrations of free iodine, as with borates, are cytotoxic and cytopathic to healthy tissue, and can have an adverse affect of reducing the body's natural defense mechanism against infection. A paper published in the British Journal of Surgery, 1986:73:95, stated "topical Povidone-Iodine not recommended for application on post appendectomy wounds". The paper was based on the results obtained from the appendicular fossa during the operations, and was predictive of the patients' likelihood to develop wound infection. In patients who had mixed aerobic and anaerobic culture results, 20% developed sepsis when PVP/I.sub.2 was used, and 7% when systemic antibodies alone were used.
PVP/I.sub.2 solutions are administered to open wound sites, as in burns, even though they are toxic, when stopping infection takes precedence over proper wound healing. Typical commercial antibacterials such as soap, Hexachlorophene, Hibiscrub, alcohol and Chlorhexidine are all water soluble and water miscible preparations which exhibit various efficacious antimicrobial properties on the skin, but all are relatively toxic upon contact with living cells.
Rosenblatt, in U.S. Pat. No. 5,071,648, polymerizes soluble PVA to form insoluble acetals in the form of foams, sheets or gels, and subsequently forms less soluble iodine complexes with these acetals with solutions of iodine, iodides, borates or their combinations. Such complexes of polyvinyl alcohol and iodine have a low solubility such that it releases iodine in a sustained and a controlled manner in an amount which will kill germ cells but not damage living tissue. An antimicrobial borate material may also be complexed with the polyvinyl alcohol. The complex may be with PVA or PVA acetal film, sponge, foam or gel and used as a wound dressing. The iodine is preferably complexed with hydroxylated polyvinyl acetal sponge and topically used. Additionally, the complex may be combined with a matrix, such as cloth or non-woven material.
Shih, in U.S. Pat. No. 5,073,614, described the preparation of strongly swellable, moderately or lightly crosslinked PVP having a predetermined aqueous swelling parameter and a defined viscosity which had effective thickener and gelling properties.
The reaction product of water soluble or water-insoluble PVP with elemental iodine, is marketed as a brown powder which contains about 11% of available iodine, i.e. active iodine, which can be titrated with sodium thiosulfate, and, in addition, contains about 5.5% of iodine in the form of iodide. At an iodine:iodide ratio of 2:1, the iodine bonding in the PVP-iodine complex is so strong that an iodine odor is no longer perceptible and a moist potassium iodide/starch paper introduced into the gas space above the PVP-iodine no longer acquires a color. In practice, the measure employed to assess whether the iodine is sufficiently firmly bonded is the partition coefficient of the iodine between an aqueous PVP-iodine solution and heptane, and this coefficient, as described, for example, in U.S. Pat. No. 3,028,300, should be about 200. Further it is necessary that in its formulations, in particular, in aqueous solution, the PVP-iodine complex should lose very little available iodine on storage, i.e. it should be very stable.
The prior art describes several methods for preparing such PVP-iodine complexes, including German Patent 1,037,075; U.S. Pat. Nos. 2,900,305; 4,402,937; 3,028,300; and 2,852,532; and German Published Application DAS 2,439,197.
In these references, very diverse measures have been described for the preparation of a stable PVP-iodine. For example, according to German Patent No. 1,037,075, the pulverulent PVP-iodine was subjected to a lengthy heat after-treatment at 90.degree.-100.degree. C.; while U.S. Pat. No. 2,900,305 proposed using a PVP having a defined moisture content for the preparation of a suitable PVP-iodine. U.S. Pat. No. 2,826,532 disclosed the addition of sodium bicarbonate; and U.S. Pat. No. 3,028,300 the addition of iodide in the form of hydrogen iodide or of an alkali metal iodide. U.S. Pat. No. 3,898,326 proposed the addition of hydrogen iodide or of an alkali metal iodide to an aqueous PVP solution, followed by reaction of the pulverulent PVP-iodide mixture, obtained from the solution after drying, with iodine. German Published Application DAS 2,439,197 stated that polyvinylpyrrolidone polymerized in an anhydrous organic solvent was particularly suitable for the preparation of a stable PVP-iodine.
The above prior art processes are also intended to permit economical preparation of a stable PVP-iodine. However, they also suffer from substantial disadvantages. According to the process described in German Patent 1,037,075, for example, heating for from 18 to 64 hours at 90.degree.-100.degree. C. to form the PVP-iodine complex was necessary to obtain a stable product having an iodine:iodide ratio of 2:1. The process described in U.S. Pat. No. 2,900,305 entailed heating PVP and iodine for 22 hours at 90.degree.-100.degree. C.
According to U.S. Pat. No. 3,028,300, heating can be dispensed with if iodide in the form of an alkali metal iodide or hydriodic acid is added to the mixture of polyvinylpyrrolidone and iodine. This process, however, does not represent an optimum, since inhomogeneous mixtures are formed, in which the iodine is only weakly bonded, and, accordingly a strong smell of iodine is present. A related process without heat treatment was proposed in U.S. Pat. No. 3,898,326 wherein iodides, e.g. as HI or NaI, were added to an aqueous polyvinylpyrrolidone solution, drying, and the pulverulent polyvinylpyrrolidone/iodide mixture reacted with iodine. However, HI causes corrosion problems on drying, while NaI increase the alkali content above the stringent requirements of the drug laws. German Published Application DAS 2,439,197 suggested a heating time of 10 hours; however to achieve a partition coefficients of about 200 it was necessary to heat for at least 20 hours.
The heating times can be greatly reduced, as disclosed in German Published Application DAS 2,818,767, PVP is reacted with elementary iodine in the presence of formic or oxalic acids, or an ammonium salt or amide of carbonic acid, formic acid or oxalic acid.
U.S. Pat. No. 4,402,937 described the preparation of the product in water rather than the solid state. The process comprised reacting PVP with elemental iodine in the presence of formic acid, oxalic acid or an ammonium salt or amide of carbonic acid, formic acid or oxalic acid, in aqueous solution.